New technologies are enabling the arrival of the much awaited affordable genome the ability to sequence an individuals or a tumors entire genome quickly and inexpensively [whole genome sequencing (WGS)]. WGS is now being offered in clinical care and is expected to become more widely used in the near future, particularly in cancer. However, this technological advance threatens to outpace our ability to use it effectively in clinical practice and to address the associated health policy issues. Our objective is to evaluate the potential benefit- risk tradeoffs of WGS from the perspectives of patients, providers, the health care delivery system, and society by using systematic and quantitative approaches. Our study aims are: 1) to analyze how patients and physicians evaluate WGS benefit-risk tradeoffs using a decision-theoretic model of the value of information and 2) to empirically assess benefit-risk tradeoffs of WGS at the health care system and societal levels. For Aim 1 we will measure and compare patient and physician preferences for WGS in participants of the first randomized clinical trial of WGS using a general population sample (MedSeq Project), which is being led by Harvard Medical School and a nationally representative sample using quantitative, statistically rigorous methods (conjoint analysis). Aim 2 will be accomplished using two sub-aims. In Aim 2a we will conduct a policy analysis of how benefit-risk tradeoffs are considered in health care decision making for WGS, including coverage/reimbursement decisions and clinical guideline development, and how they compare to those of more established genetic tests. In Aim 2b we will develop (1) a framework to conceptualize, identify, and define data needed to assess the value of WGS; and (2) a prototypical cost-effectiveness model of one likely finding from WGSidentification of Lynch syndromeusing data from Aims 1 and 2a, MedSeq, and our previous analyses. This will be the first national study to our knowledge of patient and physician preferences relevant to WGS in the general population, to compare preferences from a clinical trial to a national population, and to systematically examine implications of WGS for the health care system and society. The proposed work is significant in that it will produce evidence of how WGS can be most effectively and efficiently adopted while also understanding its limitationsinformation that will be useful to patients, providers, researchers, and policymakers. Our work will have broad impact on and implications for clinical practice and health policy and will build on the research currently being conducted by our experienced and diverse team. In sum, this study will address a significant topic using innovative adaptation of methods. The study is being proposed at the right time in the development of WGSa time when the study results will have an impact on the emerging science, when we can leverage the resources of an ongoing trial, and when we have the right team in place to conduct the research.